Prediction of germline mutations and cancer risk in the Lynch syndrome

Abstract

Context: Identifying families at high risk for the Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost.

Objective: To develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer.

Design, setting, and patients: External validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993-2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model's prediction is tailored to each individual's detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability.

Main outcome measure: Ability of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy.

Results: In the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78-0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84-1.05). This results in higher accuracy than existing alternatives and current clinical guidelines.

Conclusions: MMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.

Figure 1

Comparisons of Carrier Probability Estimation Approaches on 5 Pedigree Variations Numbers below each family member indicate current age, or age at death, for unaffected individuals and age at diagnosis for affected individual. The counselee is identified by the arrow. MS indicates microsatellite; MSI, microsatellite instability; MSS, microsatellite stable. *Information in these columns refers to MSI testing for the counselee.

Figure 2

Receiver Operating Characteristic Curves for the MMRpro and Leiden Models on the Validation Data Set Also shown are the estimated true-positive (y-axis) and false-positive (x-axis) fractions associated with the Bethesda Guidelines (BG). MSI indicates microsatellite instability.